Triple Agonists (GLP-1/GIP/Glucagon) Class Overview Monograph

Is retatrutide FDA-approved?

No. Retatrutide is not FDA-approved, and FDA has not found it safe and effective for any condition [1].

Approved GLP-1 receptor agonists such as semaglutide activate the GLP-1 receptor [4]. Tirzepatide activates GLP-1 and GIP receptors [5]. Neither has the three-receptor mechanism studied with retatrutide [2].

What does triple agonism mean?

A triple agonist is one peptide designed to activate three receptors at once: GLP-1, GIP and glucagon [2]. In rodent studies, a triple agonist reduced body weight, improved glycemic control and reversed hepatic steatosis, and it outperformed dual agonists and single agonists in those models [6].

The proposed split of effects is GLP-1 to reduce calorie intake and improve glucose control, GIP to potentiate the incretin effect and buffer the glucose-raising effect of glucagon, and glucagon to increase energy expenditure [6]. Retatrutide has balanced glucagon and GLP-1 receptor activity with more GIP receptor activity in vitro; a phase 1 study found a safety profile similar to other incretins and pharmacokinetics that supported once-weekly dosing [3].

What did the retatrutide phase 2 trial find?

The phase 2 trial enrolled 338 adults with a BMI of at least 30, or a BMI of 27 to less than 30 plus at least one weight-related condition [2]. Participants received weekly subcutaneous retatrutide 1 mg, 4 mg, 8 mg or 12 mg, or placebo, for 48 weeks. The 4 mg and 8 mg groups each included two different starting doses [2].

At 48 weeks, mean weight change was -8.7% with 1 mg, -17.1% with the combined 4 mg group, -22.8% with the combined 8 mg group, and -24.2% with 12 mg, versus -2.1% with placebo [2]. At 24 weeks, the changes were -7.2%, -12.9%, -17.3%, -17.5% and -1.6%, respectively [2].

At 48 weeks, at least 5%, 10% and 15% weight loss occurred in 92%, 75% and 60% of the 4 mg group; 100%, 91% and 75% of the 8 mg group; 100%, 93% and 83% of the 12 mg group; and 27%, 9% and 2% of the placebo group [2].

Gastrointestinal adverse events were the most common in the retatrutide groups, were dose-related, and were mostly mild to moderate [2].

How does retatrutide compare with approved weight-loss drugs?

In separate trials, semaglutide 2.4 mg produced mean weight change of -14.9% versus -2.4% with placebo at 68 weeks in 1,961 adults [7]. Tirzepatide 15 mg produced -20.9% versus -3.1% with placebo at 72 weeks in 2,539 adults [8]. Retatrutide 12 mg produced -24.2% versus -2.1% with placebo at 48 weeks in 338 adults [2].

Those numbers come from different trials with different durations, populations and analysis methods. They do not show that one drug is better than another in the same patient.

What safety information exists for retatrutide?

Retatrutide has no FDA-approved label, so it has no approved boxed warning, contraindications or dosing instructions [1]. The 48-week phase 2 trial identified gastrointestinal adverse events as the main tolerability issue; the trial does not provide long-term safety data [2].

For context, the Wegovy label carries a boxed warning about rodent thyroid C-cell tumors and warnings for acute pancreatitis, severe gastrointestinal reactions, gallbladder disease, hypoglycemia with insulin or sulfonylureas, hypersensitivity, diabetic retinopathy complications, heart rate increase and pulmonary aspiration during anesthesia or deep sedation [4]. Those are warnings for an approved GLP-1 product, not for retatrutide.

Can retatrutide be legally compounded?

FDA states retatrutide cannot be used in compounding under federal law and is not a component of an FDA-approved drug [1]. FDA has warned telehealth companies about marketing unapproved drugs such as retatrutide [1]. Compounded drugs are not FDA-approved and are not reviewed for safety, effectiveness or quality before they are marketed [1].